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Through the looking glass--a new world of proteins enabled by chemical synthesis.

Authors
  • Kent, Stephen
  • Sohma, Youhei
  • Liu, Suhuai
  • Bang, Duhee
  • Pentelute, Brad
  • Mandal, Kalyaneswar
Type
Published Article
Journal
Journal of Peptide Science
Publisher
Wiley (John Wiley & Sons)
Publication Date
Jul 01, 2012
Volume
18
Issue
7
Pages
428–436
Identifiers
DOI: 10.1002/psc.2421
PMID: 22674813
Source
Medline
License
Unknown

Abstract

'Chemical ligation'--the regioselective and chemoselective covalent condensation of unprotected peptide segments--has enabled the synthesis of polypeptide chains of more than 200 amino acids. An efficient total chemical synthesis of the insulin molecule has been devised on the basis of a key ester-linked intermediate that is chemically converted to fully active human insulin. Enzyme molecules of defined covalent structure and with full enzymatic activity have been prepared and characterized by high-resolution X-ray crystallography. A 'glycoprotein mimetic' of defined chemical structure and with a mass of 50,825 Da, has been prepared and shown to have full biological activity and improved pharmacokinetic properties. D-protein molecules that are the mirror images of proteins found in the natural world have been prepared by total chemical synthesis. Racemic protein mixtures, consisting of the D-enantiomers and L-enantiomers of a protein molecule, form highly ordered centrosymmetric crystals with great ease; this has enabled the determination of the crystal structures of recalcitrant protein molecules. A protein with a novel linear-loop covalent topology of the peptide chain has been designed and synthesized and its structure determined by facile crystallization as the quasi-racemate with the D-form of the native protein molecule.We have developed an optimized total chemical synthesis of biologically active vascular endothelial growth factor-A; total synthesis of the mirror-image protein will be used to systematically develop D-protein antagonists of this important growth factor. The total chemical synthesis of proteins is now a practical reality and enables access to a new world of protein molecules.

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